Bovine leukemia virus-derived long-noncoding RNA, AS1-S, binds to bovine hnRNPM and alters interaction properties between hnRNPM and host mRNAs.

Viruses utilize several strategies to develop latent infection and evade host immune responses. Long non-coding RNA (lncRNA), a class of non-protein encoding RNA that regulates various cellular functions by interacting with RNA binding proteins, is a key factor for viral latency because of its lack of antigenicity. Bovine leukemia virus (BLV), which belongs to the family Retroviridae, encodes the BLV-derived lncRNA AS1-S, which is a major transcript expressed in latently infected cells. We herein identified bovine hnRNPM, an RNA-binding protein located in the nucleus, as the binding partner for AS1-S using an RNA-protein pull-down assay. The pull-down assay using recombinant hnRNPM mutants showed that RNA recognition motif 1 and 2, located in the N-terminal region of bovine hnRNPM, are responsible for binding AS1-S. Furthermore, an RNA immunoprecipitation assay showed that introduction of AS1-S increased the number of mRNA that co-immunoprecipitated with bovine hnRNPM in MDBK cells. These results suggested that AS1-S could alter the interaction between hnRNPM and host mRNAs, potentially interfering with cellular functions during the initial phase of mRNA maturation in the nucleus. Since most of the identified mRNAs that exhibited increased binding to hnRNPM were correlated with the KEGG term "Pathways in cancer", AS1-S may affect proliferation and expansion of BLV-infected cells and contribute to tumor progression. ImportanceBLV infects bovine B cells and causes malignant lymphoma, resulting in severe economic losses in the livestock industry. Due to its low incidence rate and long latent period, the molecular mechanisms underlying the progression to lymphoma remain enigmatic. Several non-coding RNAs, such as miRNA and lncRNA, have recently been discovered in the BLV genome and the relationship between BLV pathogenesis and these non-coding RNAs is attracting attention. However, most of the molecular functions of these transcripts remain un-identified. To the best of our knowledge, this is the first report describing a molecular function for the BLV-derived lncRNA AS1-S. The findings reported herein reveal a novel mechanism underlying BLV pathogenesis that could provide important insights for not only BLV research but also comparative studies of retroviruses.